14-58428381-G-C

Variant names:

• chr14-58428381-G-C
• rs190089844
• NM_001329943.3:c.117G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000652326.2(KIAA0586):​c.117G>C​(p.Glu39Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E39E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIAA0586 ENST00000652326.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410
• Publications: 0 publications found

Genes affected

KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]

KIAA0586 Gene-Disease associations (from GenCC):

• Joubert syndrome 23

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short-rib thoracic dysplasia 14 with polydactyly

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with Jeune asphyxiating thoracic dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043293).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652326.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.117G>C	p.Glu39Asp	missense	Exon 1 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.153G>C	p.Glu51Asp	missense	Exon 2 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.117G>C	p.Glu39Asp	missense	Exon 1 of 32	NP_001316873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.117G>C	p.Glu39Asp	missense	Exon 1 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.72G>C	p.Glu24Asp	missense	Exon 2 of 32	ENSP00000478083.1
	KIAA0586	ENST00000261244.9	TSL:1	c.117G>C	p.Glu39Asp	missense	Exon 1 of 30	ENSP00000261244.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.041
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.078
Sift	Benign	0.39	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.34		Gain of catalytic residue at P26 (P = 0)
MVP		0.072
MPC		0.019
ClinPred		0.11	T
GERP RS		-1.6
PromoterAI		0.040	Neutral
Varity_R		0.060
gMVP		0.048
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs190089844; hg19: chr14-58895099;